scholarly journals A Survey of Strategies to Modulate the Bone Morphogenetic Protein Signaling Pathway: Current and Future Perspectives

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Jonathan W. Lowery ◽  
Brice Brookshire ◽  
Vicki Rosen
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Bmp Signaling ◽  
Protein Signaling ◽  
Bone Morphogenetic Protein Signaling ◽  
Human Organ ◽  
Morphogenetic Protein ◽  
Organ Systems ◽  
Bmp Pathway ◽  
Wide Perspective ◽  
The Relationship

Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the TGF-βfamily of ligands and are unequivocally involved in regulating stem cell behavior. Appropriate regulation of canonical BMP signaling is critical for the development and homeostasis of numerous human organ systems, as aberrations in the BMP pathway or its regulation are increasingly associated with diverse human pathologies. In this review, we provide a wide-perspective on strategies that increase or decrease BMP signaling. We briefly outline the current FDA-approved approaches, highlight emerging next-generation technologies, and postulate prospective avenues for future investigation. We also detail how activating other pathways may indirectly modulate BMP signaling, with a particular emphasis on the relationship between the BMP and Activin/TGF-βpathways.

scholarly journals Cooperative Inhibition of Bone Morphogenetic Protein Signaling by Smurf1 and Inhibitory Smads

2003 ◽  
Vol 14 (7) ◽  
pp. 2809-2817 ◽  
Author(s):  
Gyo Murakami ◽  
Tetsuro Watabe ◽  
Kunio Takaoka ◽  
Kohei Miyazono ◽  
Takeshi Imamura
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Type I ◽  
Protein Signaling ◽  
Reporter Construct ◽  
Bone Morphogenetic Protein Signaling ◽  
Morphogenetic Protein

Smad ubiquitin regulatory factor (Smurf) 1 binds to receptor-regulated Smads for bone morphogenetic proteins (BMPs) Smad1/5 and promotes their degradation. In addition, Smurf1 associates with transforming growth factor-β type I receptor through the inhibitory Smad (I-Smad) Smad7 and induces their degradation. Herein, we examined whether Smurf1 negatively regulates BMP signaling together with the I-Smads Smad6/7. Smurf1 and Smad6 cooperatively induced secondary axes in Xenopus embryos. Using a BMP-responsive promoter-reporter construct in mammalian cells, we found that Smurf1 cooperated with I-Smad in inhibiting BMP signaling and that the inhibitory activity of Smurf1 was not necessarily correlated with its ability to bind to Smad1/5 directly. Smurf1 bound to BMP type I receptors via I-Smads and induced ubiquitination and degradation of these receptors. Moreover, Smurf1 associated with Smad1/5 indirectly through I-Smads and induced their ubiquitination and degradation. Smurf1 thus controls BMP signaling with and without I-Smads through multiple mechanisms.

scholarly journals Bone morphogenetic protein signaling in inflammation

2019 ◽  
Vol 244 (2) ◽  
pp. 147-156 ◽  
Author(s):  
David H Wu ◽  
Antonis K Hatzopoulos
Keyword(s):  
Bone Morphogenetic Protein ◽  
Bmp Signaling ◽  
Therapeutic Interventions ◽  
Protein Signaling ◽  
Bone Morphogenetic Protein Signaling ◽  
Morphogenetic Protein ◽  
Therapeutic Value ◽  
Organ Systems ◽  
Different Tissues

Bone morphogenetic protein signaling has long been established as a crucial pathway during embryonic development. In recent years, our knowledge of the function of bone morphogenetic protein signaling has expanded dramatically beyond solely its important role in development. Today, the pathway is known to have important homeostatic functions across multiple different tissues in the adult. Even more importantly, bone morphogenetic protein signaling is now known to function as a driver of diseases in the adult spanning different organ systems. In this review, we will explore the functions of bone morphogenetic protein signaling in diseases of inflammation. Through this exploration, we will highlight the value and challenges in targeting bone morphogenetic protein signaling for therapeutic interventions. Impact statement By compiling findings from recent studies, this review will garner novel insight on the dynamic and complex role of BMP signaling in diseases of inflammation, highlighting the specific roles played by both individual ligands and endogenous antagonists. Ultimately, this summary will help inform the high therapeutic value of targeting this pathway for modulating diseases of inflammation.

scholarly journals Membrane targeting of inhibitory Smads through palmitoylation controls TGF-β/BMP signaling

2017 ◽  
Vol 114 (50) ◽  
pp. 13206-13211 ◽  
Author(s):  
Wenqing Li ◽  
Weini Li ◽  
Lihui Zou ◽  
Shanming Ji ◽  
Chaoyi Li ◽  
...  
Keyword(s):  
Cellular Membrane ◽  
Bmp Signaling ◽  
Tissue Homeostasis ◽  
Membrane Association ◽  
Type I ◽  
Protein Signaling ◽  
Bone Morphogenetic Protein Signaling ◽  
Stem Cell Regulation ◽  
Morphogenetic Protein ◽  
Signaling Activity

TGF-β/BMP (bone morphogenetic protein) signaling pathways play conserved roles in controlling embryonic development, tissue homeostasis, and stem cell regulation. Inhibitory Smads (I-Smads) have been shown to negatively regulate TGF-β/BMP signaling by primarily targeting the type I receptors for ubiquitination and turnover. However, little is known about how I-Smads access the membrane to execute their functions. Here we show that Dad, the Drosophila I-Smad, associates with the cellular membrane via palmitoylation, thereby targeting the BMP type I receptor for ubiquitination. By performing systematic biochemistry assays, we characterized the specific cysteine (Cys556) essential for Dad palmitoylation and membrane association. Moreover, we demonstrate that dHIP14, a Drosophila palmitoyl acyl-transferase, catalyzes Dad palmitoylation, thereby inhibiting efficient BMP signaling. Thus, our findings uncover a modification of the inhibitory Smads that controls TGF-β/BMP signaling activity.

scholarly journals Unraveling the Connection between Fibroblast Growth Factor and Bone Morphogenetic Protein Signaling

2018 ◽  
Vol 19 (10) ◽  
pp. 3220 ◽  
Author(s):  
Anna Schliermann ◽  
Joachim Nickel
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Cellular Responses ◽  
Dependent Manner ◽  
Fibroblast Growth ◽  
Protein Signaling ◽  
Fgf Signaling ◽  
Bone Morphogenetic Protein Signaling ◽  
Cellular Functions ◽  
Morphogenetic Protein ◽  
Signal Regulation

Ontogeny of higher organisms as well the regulation of tissue homeostasis in adult individuals requires a fine-balanced interplay of regulating factors that individually trigger the fate of particular cells to either stay undifferentiated or to differentiate towards distinct tissue specific lineages. In some cases, these factors act synergistically to promote certain cellular responses, whereas in other tissues the same factors antagonize each other. However, the molecular basis of this obvious dual signaling activity is still only poorly understood. Bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs) are two major signal protein families that have a lot in common: They are both highly preserved between different species, involved in essential cellular functions, and their ligands vastly outnumber their receptors, making extensive signal regulation necessary. In this review we discuss where and how BMP and FGF signaling cross paths. The compiled data reflect that both factors synchronously act in many tissues, and that antagonism and synergism both exist in a context-dependent manner. Therefore, by challenging a generalization of the connection between these two pathways a new chapter in BMP FGF signaling research will be introduced.

scholarly journals Processing of hemojuvelin requires retrograde trafficking to the Golgi in HepG2 cells

Blood ◽  
2009 ◽  
Vol 113 (8) ◽  
pp. 1786-1793 ◽  
Author(s):  
Julia E. Maxson ◽  
Caroline A. Enns ◽  
An-Sheng Zhang
Keyword(s):  
Plasma Membrane ◽  
Bone Morphogenetic Proteins ◽  
Iron Homeostasis ◽  
Soluble Form ◽  
Protein Signaling ◽  
Bone Morphogenetic Protein Signaling ◽  
Glycosylphosphatidylinositol Anchor ◽  
Retrograde Trafficking ◽  
Hepcidin Expression ◽  
Morphogenetic Protein

Abstract Hemojuvelin (HJV) was recently identified as a critical regulator of iron homeostasis. It is either associated with cell membranes through a glycosylphosphatidylinositol anchor or released as a soluble form. Membrane-anchored HJV acts as a coreceptor for bone morphogenetic proteins and activates the transcription of hepcidin, a hormone that regulates iron efflux from cells. Soluble HJV antagonizes bone morphogenetic protein signaling and suppresses hepcidin expression. In this study, we examined the trafficking and processing of HJV. Cellular HJV reached the plasma membrane without obtaining complex oligosaccharides, indicating that HJV avoided Golgi processing. Secreted HJV, in contrast, has complex oligosaccharides and can be derived from HJV with high-mannose oligosaccharides at the plasma membrane. Our results support a model in which retrograde trafficking of HJV before cleavage is the predominant processing pathway. Release of HJV requires it to bind to the transmembrane receptor neogenin. Neogenin does not, however, play a role in HJV trafficking to the cell surface, suggesting that it could be involved either in retrograde trafficking of HJV or in cleavage leading to HJV release.

scholarly journals Scale invariance of BMP signaling gradients in zebrafish

2018 ◽  
Author(s):  
Yan Huang ◽  
David Umulis
Keyword(s):  
Scale Invariance ◽  
Bmp Signaling ◽  
Spatial Patterning ◽  
Protein Signaling ◽  
Wild Type ◽  
Bone Morphogenetic Protein Signaling ◽  
Cross Sectional ◽  
Morphogenetic Protein ◽  
Core Questions ◽  
Gradient Scaling

In both vertebrates and invertebrates, spatial patterning along the Dorsal-ventral (DV) embryonic axis depends on a morphogen gradient of Bone Morphogenetic Protein signaling. Scale invariance of DV patterning by BMPs has been found in both vertebrates and invertebrates, however the mechanisms that regulate gradient scaling remain controversial. To obtain quantitative data that can be used to address core questions of scaling, we introduce a method to tune the size of zebrafish embryos by reducing varying amounts of vegetal yolk. We quantified the BMP signaling gradient in wild-type and perturbed embryos and found that the system scales for reductions in cross-sectional perimeter of up to 30%. Furthermore, we found that the degree of scaling for intraspecies scaling within zebrafish is greater than that between Danioninae species.

scholarly journals NRAGE Mediates p38 Activation and Neural Progenitor Apoptosis via the Bone Morphogenetic Protein Signaling Cascade

2005 ◽  
Vol 25 (17) ◽  
pp. 7711-7724 ◽  
Author(s):  
Stephen E. Kendall ◽  
Chiara Battelli ◽  
Sarah Irwin ◽  
Jane G. Mitchell ◽  
Carlotta A. Glackin ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Neural Progenitor ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Signaling Cascade ◽  
Protein Signaling ◽  
Neocortical Development ◽  
Molecular Events ◽  
Morphogenetic Protein ◽  
And Function

ABSTRACT Understanding the molecular events that govern neural progenitor lineage commitment, mitotic arrest, and differentiation into functional progeny are germane to our understanding of neocortical development. Members of the family of bone morphogenetic proteins (BMPs) play pivotal roles in regulating neural differentiation and apoptosis during neurogenesis through combined actions involving Smad and TAK1 activation. We demonstrate that BMP signaling is required for the induction of apoptosis of neural progenitors and that NRAGE is a mandatory component of the signaling cascade. NRAGE possesses the ability to bind and function with the TAK1-TAB1-XIAP complex facilitating the activation of p38. Disruption of NRAGE or any other member of the noncanonical signaling cascaded is sufficient to block p38 activation and thus the proapoptotic signals generated through BMP exposure. The function of NRAGE is independent of Smad signaling, but the introduction of a dominant-negative Smad5 also rescues neural progenitor apoptosis, suggesting that both canonical and noncanonical pathways can converge and regulate BMP-mediated apoptosis. Collectively, these results establish NRAGE as an integral component in BMP signaling and clarify its role during neural progenitor development.

scholarly journals The Role of BMP Signaling in Osteoclast Regulation

2021 ◽  
Vol 9 (3) ◽  
pp. 24
Author(s):  
Brian Heubel ◽  
Anja Nohe
Keyword(s):  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Bone Diseases ◽  
Bmp Signaling ◽  
Bone Homeostasis ◽  
Direct Stimulation ◽  
Federal Drug Administration ◽  
Bmp Pathway ◽  
Stimulation Of

The osteogenic effects of Bone Morphogenetic Proteins (BMPs) were delineated in 1965 when Urist et al. showed that BMPs could induce ectopic bone formation. In subsequent decades, the effects of BMPs on bone formation and maintenance were established. BMPs induce proliferation in osteoprogenitor cells and increase mineralization activity in osteoblasts. The role of BMPs in bone homeostasis and repair led to the approval of BMP2 by the Federal Drug Administration (FDA) for anterior lumbar interbody fusion (ALIF) to increase the bone formation in the treated area. However, the use of BMP2 for treatment of degenerative bone diseases such as osteoporosis is still uncertain as patients treated with BMP2 results in the stimulation of not only osteoblast mineralization, but also osteoclast absorption, leading to early bone graft subsidence. The increase in absorption activity is the result of direct stimulation of osteoclasts by BMP2 working synergistically with the RANK signaling pathway. The dual effect of BMPs on bone resorption and mineralization highlights the essential role of BMP-signaling in bone homeostasis, making it a putative therapeutic target for diseases like osteoporosis. Before the BMP pathway can be utilized in the treatment of osteoporosis a better understanding of how BMP-signaling regulates osteoclasts must be established.

Sign in / Sign up

Export Citation Format

Share Document